Elucidating the interaction between MTDH, an oncoprotein with UPR signalling molecule IRE1α under cellular stress

IRE1α (inositol-requiring enzyme type 1) is one of the primary sensor arms of UPR signalling pathway with special ability to detect unfolded/misfolded proteins in the ER lumen. It is a bifunctional protein with kinase and endoribonuclease activity, playing a crucial role in managing ER stress. The C-terminal domain of IRE1α, facing towards the cytosol, acts as a scaffold for various effector proteins to regulate IRE1α activity. Our previous mass spectroscopic studies has revealed Metadherin (MTDH) as one of the binding partner of IRE1α. MTDH is an oncoprotein implicated in cancer metastasis and survival, affecting various cell signalling pathways to drive cancer progression. The presence of this protein in the immune complex in our IRE1α driven immunoprecipitation experiments of stressed cells was significant as the UPR is believed to facilitate cell apoptosis during prolonged stress, which is compromised in cancerous cells to allow metastasis. This prompted us to study and explore the interaction between the two proteins IRE1α and MTDH, a positive interaction pointing to a cross talk between the homeostatic and metastatic signalling pathways. Various experiments, including co-immunoprecipitation, Yeast-two Hybrid assay, and bioinformatics analyses established a positive interaction between IRE1α and MTDH supporting the argument that these proteins interact and might influence IRE1α’s role in cellular stress response.